Racemic threo-methylphenidate or methyl (R*,R*)-α-phenyl-2-piperidineacetate, having the formula: and its salts are CNS (central nervous system) stimulants that are chemically and pharmacologically similar to the amphetamines. threo-Methylphenidate's CNS actions are milder than those of the amphetamines and have more noticeable effects on mental activities than on motor activities.
Methylphenidate has two chiral centers, but the drug used in therapy comprises only the threo pair of d- and 1-enantiomers. Methylphenidate is marketed as a racemic mixture of 1-threo-methylphenidate and d-threo-methylphenidate, where the d-threo-Methylphenidate is considered to be more potent than the 1-threo-enantiomer.
A commercially available drug is sold under the name Ritalin™ (Novartis) and it consists of threo-methylphenidate in the form of the hydrochloride salt. This product is orally administered and clinically used in the treatment of attention-deficit hyperactivity disorders (ADHD) in children and used for the treatment of narcolepsy and depression in adults.
It has been reported by Szporny (1961) that among racemic mixtures of threo and erythro diastereomers of methylphenidate, only threo-isomer displays stimulant properties. In U.S. Pharmacopoeia USP 26 it is indicated that the content of erythro isomer in a racemic mixture of threo/erythro methylphenidate hydrochloride should not be higher than 1% in order to possess desired properties of active pharmaceutical ingredient (API).
Synthetic methods for the preparation of racemic mixtures of threo- and erythro-α-phenyl-2-piperidineacetamides as raw materials for the preparation of threo-methylphenidate were described in U.S. Pat. Nos. 2,507,631, 2,838,519, 2,957,880 and 5,936,091, in WO 01/27070 and by Panizzon (1944) and Patric (1982). These methods include using sodium amide as base in the nucleophilic substitution of chlorine in 2-chloropyridine with phenylacetonitrile followed by hydrolysis of the formed nitrile and reduction of the pyridine ring to a piperidine one by hydrogenation on PtO2 catalyst to obtain erythro-enriched α-phenyl-2-piperidineacetamide, which is then subjected to epimerization, hydrolysis, and esterification of threo-ritalinic acid as shown in Scheme 1: 
Alternatively, 2-bromopyridine was used instead of 2-chloropyridine by Deutsch (1996).
Other synthetic route for the preparation of threo-methylphenidate hydrochloride, as described by Axten (1998) and in WO 99/36403, is based on cyclization of easily available 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone to (R*,R*)-enriched 7-phenyl-1-azabicyclo[4.2.0]octan-8-one followed by conversion of the obtained β-lactam to threo-methylphenidate hydrochloride as described in Scheme 2: 
t-BuOK used in the first step of the synthesis described in Scheme 2 above is flammable and dangerous to handle in industrial-scale processes. In addition, the first step shown in Scheme 2 is expensive and the yield for obtaining the β-lactam product is relatively low (about 60%).